PICCASSO: Combined PD-1 and CCR5 Inhibition for the Treatment of Refractory Microsatellite Stable mCRC

• Sponsor: University Hospital Heidelberg (Other)
• Overall Status: Completed
• CT.gov ID: NCT03274804
• Collaborator: Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest (Other)
• Enrollment: 20
• Location: 1
• Arm: 1
• Actual Duration (Months): 23
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This is a monocentric, single arm, prospective, open-label trial of a combination treatment consisting of pembrolizumab and maraviroc in previously treated subjects who have refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC).

Condition or Disease	Intervention/Treatment	Phase
Metastatic Colorectal Cancer; MSS	Biological: Pembrolizumab; Drug: Maraviroc	Phase 1

Detailed Description

Eligible subjects will receive pembrolizumab beginning on Day 1 of each 3-week dosing cycle (d1, qd22) together with maraviroc administered perorally on day 1 to 21 of each cycle (d1-21; qd22).

Treatment with pembrolizumab / maraviroc combination will continue until progressive disease (PD), unacceptable adverse events (AEs), intercurrent illness that prevents further administration of treatment, investigator's decision to withdraw the subject, subject withdraws consent, pregnancy of the subject, noncompliance with trial treatment or procedure requirements, administrative reasons requiring cessation of treatment, or completion of treatment per protocol.

Subjects with a treatment response or stable disease after completion of the first treatment phase of eight cycles (core treatment period) will be offered, at the discretion of the investigator, participation in a maintenance phase consisting of up to 24 additional treatment cycles of pembrolizumab monotherapy (total treatment duration up to 24 months).

Subjects who discontinue for reasons other than PD will have post-treatment follow-up for disease status until PD, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. All subjects will be followed for overall survival (OS) until death, withdrawal of consent, loss to follow-up, or the end of the study.

After the end of treatment, each subject will be followed for 30 days for AE monitoring. Serious adverse events (SAEs) and AEs of special interest (AESIs) will be collected for 90 days after the end of treatment or for 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Trial of Combined PD-1 Inhibition (Pembrolizumab) and CCR5 Inhibition (Maraviroc) for the Treatment of Refractory Microsatellite Stable (MSS) Metastatic Colorectal Cancer (mCRC)
• Actual Study Start Date: Apr 1, 2018
• Actual Primary Completion Date: Mar 1, 2020
• Actual Study Completion Date: Mar 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single arm, prospective, open-label trial Eligible subjects will receive pembrolizumab beginning on Day 1 of each 3-week dosing cycle (d1, qd22) together with maraviroc administered perorally on day 1 to 21 of each cycle (d1-21; qd22).	Biological: Pembrolizumab; Eligible subjects will receive pembrolizumab beginning on Day 1 of each 3-week dosing cycle (d1, qd22); Other Names: Keytruda ; Drug: Maraviroc; Maraviroc will be administered perorally on day 1 to 21 of each cycle (d1-21; qd22); Other Names: Celsentri

Outcome Measures

Primary Outcome Measures

1. Feasibility Rate of a Combined Therapy [After core treatment period of 8 cycles (each cycle is 21 days)]

   Defined as the rate of patients receiving the protocol treatment according to the planned schedule without occurrence of at least one of the following events: Study treatment-related Grade ≥ 3 immune-related abnormalities; Study treatment-related Grade ≥ 4 AEs of any aetiology; Any toxic event leading to the premature withdrawal of protocol treatment

Secondary Outcome Measures

1. Safety and Toxicity of a Combined Therapy Based on Subjects Who Experienced Toxicities [After core treatment period of 8 cycles (each cycle is 21 days)]

   The primary safety analysis will be based on subjects who experienced toxicities as defined by the current National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, v4.0; Section 11.2). The attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant medications administered will be recorded.

2. Efficacy Endpoint: Disease Control Rate [through study completion (20 months)]

   Determine DCR defined as percentage of patients displaying CR/PR or SD as best response according to the RECIST criteria version 1.1.

3. Efficacy Endpoint: Objective Response Rate [through study completion (20 months)]

   ORR and immune related (ir) ORR (irORR) will be analyzed.

4. Efficacy Endpoint: Progression-free Survival [through study completion (20 months)]

   Individual PFS will be analyzed.

5. Overall Survival [through study completion (20 months)]

   Individual OS will be analyzed.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Histologically confirmed metastatic colorectal cancer. Microsatellite stability (MSS) is confirmed by PCR or immunohistochemistry.

2. Patient failed standard therapy or is intolerable towards standard therapy which must include a fluoropyrimidine, oxaliplatin, irinotecan, an antiangiogenic monoclonal antibody (e.g. bevacizumab, aflibercept, ramucirumab), an EGFR inhibitor in case of RAS/BRAF wildtype tumors and optional regorafenib or TAS 102

3. Measurable disease as per RECIST 1.1

4. Metastatic lesion accessible for repetitive biopsies and patient willing to provide tissue from newly obtained biopsies. Patients without accessible lesions might be enrolled after discussion with the principle investigator.

5. ECOG performance status 0 or 1

6. Adequate hematological, hepatic and renal function parameters:

• Leucocytes> 3.000/μl

• Hemoglobin >9 g/dl

• Thrombocytes > 100.000/μl

• Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or GFR ≥60 mL/min for subject with creatinine levels > 1.5 x institutional ULN

• Serum total bilirubin ≤ 1.5 x upper limit of normal or direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN

• AST and ALT ≤ 2.5 x upper limit of normal (or ≤ 5 x if liver metastases are present)

• Albumin ≥ 2.5 mg/dL

1. Adequate coagulation functions as defined by International Normalized Ratio (INR) ≤1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin/ phenprocoumon must be switched to low molecular weight heparin and have achieved stable coagulation profile.

2. Female and male patients' ≥ 18 years. Patients in reproductive age must be willing to use adequate contraception during the study and 4 months after the end of the study (appropriate contraception is defined as surgical sterilization (e.g., bilateral tubal ligation, vasectomy), hormonal contraception (implantable, patch, oral), and doublebarrier methods (any double combination of: IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap)). Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the subject's preferred and usual lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception. Female patients with childbearing potential need to have a negative pregnancy test within 7 days before study start.

3. Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures.

Exclusion Criteria:

1. Inability to understand the aims of the study and/or protocol procedures

2. Hypersensitivity towards pembrolizumab, maraviroc, or any ingredients of the formulations administered

3. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies

4. Any other concurrent antineoplastic treatment including irradiation (local radiation of single non-target lesions for palliation only allowed)

5. Active autoimmune disease requiring immunosuppressive therapy

6. Any condition requiring continuous systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 2 weeks prior to first dose of study treatment. Inhaled or topical steroids and physiological replacement doses of up to 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.

7. Secondary malignant disease during the last 5 years (exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy).

8. Clinical relevant comorbidity also including significant psychiatric disease

9. Clinically significant active coronary heart disease, cardiomyopathy or congestive heart failure, NYHA III-IV

10. Cardiocirculatory insufficiency with hypotension (systolic blood pressure <100 mmHg)

11. Cirrhosis of the liver (Child > Grade A), pronounced alcohol abuse with anticipated detoxification, severe pulmonary infection with considerable reduction of pulmonary function

12. Prior allogeneic bone marrow transplantation

13. Prior treatment with anti-PD-1, anti-PD-L1, or anti-PD-L2 therapeutic antibody

14. Administration of a live, attenuated vaccine within four weeks prior to start of maintenance treatment or anticipation that such a live attenuated vaccine will be required during the remainder of the study Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

15. Chronic intake of drugs that lead to known interference with Maraviroc metabolism through strong Cytochrome P450 3A4 (CYP3A4) interaction: e.g. Rifampicin, Rifabutin, Clarithromycin, Telithromycin, Ketoconazole, Itraconazole, Fluconazole, Hypericum perforatum (St. John's Worth /Johanniskraut) or any strong CYP3A4 inducing or inhibiting drug (See Section 5.5.2)

16. Positive test for human immunodeficiency virus (HIV) or HIV infection

17. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test) or hepatitis C. Note: Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen antibody test) are eligible.

18. Active or latent tuberculosis

19. Clinically active brain metastases, defined as untreated symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms.

Subjects with treated brain metastases that are no longer symptomatic and require no treatment with steroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy and have no evidence of disease progression on imaging studies (MRI/CT scan).

1. On-treatment participation in another clinical study in the period 30 days prior to start of study treatment and during the study

2. Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)

3. Pregnancy or lactation

4. Known history of, or any evidence of active, non-infectious pneumonitis or interstitial lung disease.

5. Active infection requiring systemic therapy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Center for Tumor Diseases, University Hospital Heidelberg	Heidelberg		Germany

Sponsors and Collaborators

• University Hospital Heidelberg
• Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest

Investigators

• Principal Investigator: Dirk Jäger, Prof., NCT, Med Oncology, University Hospital Heidelberg

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 1, 2018

More Information

Publications

None provided.

• Responsible Party: Dirk Jäger, Prof. Dr., University Hospital Heidelberg
• ClinicalTrials.gov Identifier: NCT03274804
• Other Study ID Numbers: PICCASSO
• First Posted: Sep 7, 2017
• Last Update Posted: Jun 7, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Colorectal Neoplasms; Maraviroc; Pembrolizumab

Study Results

Participant Flow

Arm/Group Title	Single Arm, Prospective, Open-label Trial
Arm/Group Description	Eligible subjects will receive pembrolizumab beginning on Day 1 of each 3-week dosing cycle (d1, qd22) together with maraviroc administered perorally on day 1 to 21 of each cycle (d1-21; qd22). Pembrolizumab: Eligible subjects will receive pembrolizumab beginning on Day 1 of each 3-week dosing cycle (d1, qd22) Maraviroc: Maraviroc will be administered perorally on day 1 to 21 of each cycle (d1-21; qd22)
Period Title: Overall Study
STARTED	20
COMPLETED	20
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Study Treatment Arm
Arm/Group Description	All enrolled subjects received pembrolizumab 200 mg IV on day one every three weeks (d1, qd22; Q3W) plus maraviroc 2 x 300 mg p.o. daily as combination therapy in an unblinded fashion.
Overall Participants	20
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	11 55%
>=65 years	9 45%
Age (years) [Median (Standard Deviation) ]
Median (Standard Deviation) [years]	61 (8.94)
Sex: Female, Male (Count of Participants)
Female	13 65%
Male	7 35%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	19 95%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
Germany	20 100%

Outcome Measures

1. Primary Outcome

Title	Feasibility Rate of a Combined Therapy
Description	Defined as the rate of patients receiving the protocol treatment according to the planned schedule without occurrence of at least one of the following events: Study treatment-related Grade ≥ 3 immune-related abnormalities; Study treatment-related Grade ≥ 4 AEs of any aetiology; Any toxic event leading to the premature withdrawal of protocol treatment
Time Frame	After core treatment period of 8 cycles (each cycle is 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm, Prospective, Open-label Trial
Arm/Group Description	All enrolled subjects received pembrolizumab 200 mg IV on day one every three weeks (d1, qd22; Q3W) plus maraviroc 2 x 300 mg p.o. daily as combination therapy in an unblinded fashion.
Measure Participants	19
Count of Participants [Participants]	18 90%

2. Secondary Outcome

Title	Safety and Toxicity of a Combined Therapy Based on Subjects Who Experienced Toxicities
Description	The primary safety analysis will be based on subjects who experienced toxicities as defined by the current National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, v4.0; Section 11.2). The attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant medications administered will be recorded.
Time Frame	After core treatment period of 8 cycles (each cycle is 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Treatment Arm
Arm/Group Description	All enrolled subjects received pembrolizumab 200 mg IV on day one every three weeks (d1, qd22; Q3W) plus maraviroc 2 x 300 mg p.o. daily as combination therapy in an unblinded fashion.
Measure Participants	20
Count of Participants [Participants]	20 100%

3. Secondary Outcome

Title	Efficacy Endpoint: Disease Control Rate
Description	Determine DCR defined as percentage of patients displaying CR/PR or SD as best response according to the RECIST criteria version 1.1.
Time Frame	through study completion (20 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Treatment Arm
Arm/Group Description	All enrolled subjects received pembrolizumab 200 mg IV on day one every three weeks (d1, qd22; Q3W) plus maraviroc 2 x 300 mg p.o. daily as combination therapy in an unblinded fashion.
Measure Participants	19
Count of Participants [Participants]	1 5%

4. Secondary Outcome

Title	Efficacy Endpoint: Objective Response Rate
Description	ORR and immune related (ir) ORR (irORR) will be analyzed.
Time Frame	through study completion (20 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm, Prospective, Open-label Trial
Arm/Group Description	All enrolled subjects received pembrolizumab 200 mg IV on day one every three weeks (d1, qd22; Q3W) plus maraviroc 2 x 300 mg p.o. daily as combination therapy in an unblinded fashion.
Measure Participants	19
Count of Participants [Participants]	1 5%

5. Secondary Outcome

Title	Efficacy Endpoint: Progression-free Survival
Description	Individual PFS will be analyzed.
Time Frame	through study completion (20 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Treatment Arm
Arm/Group Description	All enrolled subjects received pembrolizumab 200 mg IV on day one every three weeks (d1, qd22; Q3W) plus maraviroc 2 x 300 mg p.o. daily as combination therapy in an unblinded fashion.
Measure Participants	19
Median (95% Confidence Interval) [weeks]	9

6. Secondary Outcome

Title	Overall Survival
Description	Individual OS will be analyzed.
Time Frame	through study completion (20 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Treatment Arm
Arm/Group Description	All enrolled subjects received pembrolizumab 200 mg IV on day one every three weeks (d1, qd22; Q3W) plus maraviroc 2 x 300 mg p.o. daily as combination therapy in an unblinded fashion.
Measure Participants	19
Median (95% Confidence Interval) [Time until event, month]	9

Adverse Events

Time Frame	From the time of treatment allocation through 30 days following discontinuation of treatment, up to 20 months, all adverse events must be reported by the investigator.
Arm/Group Title	Study Treatment Arm
Arm/Group Description	The primary safety analysis will be based on subjects who experienced toxicities as defined by the current National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, v4.0; Section 11.2). The attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant medications administered will be recorded.
All Cause Mortality
	Study Treatment Arm
	Affected / at Risk (%)	# Events
Total	0/20 (0%)
Serious Adverse Events
	Study Treatment Arm
	Affected / at Risk (%)	# Events
Total	4/20 (20%)
Infections and infestations
Infections and infestations - Other	1/20 (5%)	1
Catheter related infection	1/20 (5%)	1
Metabolism and nutrition disorders
Hyperglycemia	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	Study Treatment Arm
	Affected / at Risk (%)	# Events
Total	20/20 (100%)
Blood and lymphatic system disorders
Anemia	1/20 (5%)
Blood and lymphatic system disorders - Other, specify	1/20 (5%)
Ear and labyrinth disorders
Ear and labyrinth disorders - Other, specify	1/20 (5%)
Endocrine disorders
Hypothyroidism	1/20 (5%)
Eye disorders
Conjunctivitis	1/20 (5%)
Eye disorders - Other, specify	1/20 (5%)
Keratitis	1/20 (5%)
Gastrointestinal disorders
Abdominal pain	1/20 (5%)
Anal hemorrhage	1/20 (5%)
Ascites	1/20 (5%)
Bloating	1/20 (5%)
Constipation	1/20 (5%)
Diarrhea	1/20 (5%)
Dysphagia	1/20 (5%)
Gastrointestinal disorders - Other, specify	1/20 (5%)
Hemorrhoidal hemorrhage	1/20 (5%)
Mucositis oral	1/20 (5%)
Nausea	1/20 (5%)
Rectal hemorrhage	1/20 (5%)
Stomach pain	1/20 (5%)
Vomiting	1/20 (5%)
General disorders
Chills	1/20 (5%)
Edema limbs	1/20 (5%)
Fatigue	1/20 (5%)
Fever	1/20 (5%)
General disorders and administration site conditions - Other, specify	1/20 (5%)
Localized edema	1/20 (5%)
Non-cardiac chest pain	1/20 (5%)
Pain	1/20 (5%)
Hepatobiliary disorders
Gallbladder obstruction	1/20 (5%)
Infections and infestations
Bronchial infection	1/20 (5%)
Catheter related infection	1/20 (5%)
Infections and infestations - Other, specify	1/20 (5%)
Nail infection	1/20 (5%)
Rash pustular	1/20 (5%)
Salivary gland infection	1/20 (5%)
Tooth infection	1/20 (5%)
Urinary tract infection	1/20 (5%)
Investigations
Alanine aminotransferase increased	1/20 (5%)
Aspartate aminotransferase increased	1/20 (5%)
Blood bilirubin increased	1/20 (5%)
Creatinine increased	1/20 (5%)
Investigations - Other, specify	1/20 (5%)
Weight gain	1/20 (5%)
Metabolism and nutrition disorders
Anorexia	1/20 (5%)
Dehydration	1/20 (5%)
Hyperglycemia	1/20 (5%)
Hypernatremia	1/20 (5%)
Hypokalemia	1/20 (5%)
Metabolism and nutrition disorders - Other, specify	1/20 (5%)
Musculoskeletal and connective tissue disorders
Back pain	1/20 (5%)
Bone pain	1/20 (5%)
Chest wall pain	1/20 (5%)
Flank pain	1/20 (5%)
Musculoskeletal and connective tissue disorder - Other, specify	1/20 (5%)
Pain in extremity	1/20 (5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/20 (5%)
Nervous system disorders
Headache	1/20 (5%)
Peripheral sensory neuropathy	1/20 (5%)
Tremor	1/20 (5%)
Psychiatric disorders
Insomnia	1/20 (5%)
Renal and urinary disorders
Renal and urinary disorders - Other, specify	1/20 (5%)
Urinary frequency	1/20 (5%)
Urinary incontinence	1/20 (5%)
Urinary retention	1/20 (5%)
Reproductive system and breast disorders
Reproductive system and breast disorders - Other, specify	1/20 (5%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/20 (5%)
Cough	1/20 (5%)
Dyspnea	1/20 (5%)
Pleural effusion	1/20 (5%)
Pneumonitis	1/20 (5%)
Sore throat	1/20 (5%)
Wheezing	1/20 (5%)
Skin and subcutaneous tissue disorders
Alopecia	1/20 (5%)
Dry skin	1/20 (5%)
Pruritus	1/20 (5%)
Rash acneiform	1/20 (5%)
Rash maculo-papular	1/20 (5%)
Skin and subcutaneous tissue disorders - Other, specify	1/20 (5%)
Vascular disorders
Flushing	1/20 (5%)
Hot flashes	1/20 (5%)
Hypertension	1/20 (5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.